Influenza A viruses (IAV) are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S. and 40 million people worldwide. Pandemics in 1957 and 1968, while less severe, were also of major public health importance. A novel influenza A virus of swine origin became pandemic in 2009, causing the first pandemic in 41 years. In addition, annual epidemic influenza cases are also very significant resulting in up to 49,000 deaths in the U.S. annually. Clinical natural history studies to compare natural influenza virus infections in immunocompromised, non-immunocompromised, and other high-risk populations, including pregnant women, are important to better treat and prevent influenza virus-infected patients. We plan to ultimately recruit up to 1000 patients with influenza virus infection. Recruitment occurred in both inpatient and outpatient settings at multiple sites including the NIH Clinical Center, Suburban Hospital and the Washington Hospital Center. Careful clinical evaluation, analysis of viruses collected from patients, and studies of the immune response of the patients is being performed. An ongoing effort is continuing to analyze the data collected over the past 4 years of this study and a report on these data is planned within the next 6 months. As an adjunct to the natural history studies, the first human volunteer influenza virus challenge study to be performed in the U.S. in over a decade was completed this past year using a 2009 influenza A/H1N1 virus under an FDA-approved IND. A healthy volunteer screening study continued at the Clinical Center to identify patients who will qualify and be available for current and future challenge studies in the upcoming months. The initial challenge study protocol, a dose finding study, has been evaluated and a manuscript is in peer review. Additional viral seed stocks of recent H3N2 and H1N1 viruses are being prepared. A second human volunteer influenza virus challenge study evaluating correlates of protection is currently underway. Another human volunteer influenza virus challenge study will evaluate a novel therapeutic to treat influenza infection in a phase II study will begin in the coming months.